The major goal of this application is to identify the molecular and genetic determinants which control/promote the invasive growth and metastasis of head and neck squamous cell carcinomas (HNSCC). The poor prognosis of patients with HNSCC is due to the high invasive growth potential of these tumors, resulting in early regional lymph node and subsequent distant metastasis. The invasive growth, which is instrumental in invasion and metastasis of HNSCC, is a complex multistage process in which cell proliferation combines with cell-cell dissociation and movement, matrix degradation and survival. Although the gene expression profiling has provided important information regarding HNSCC-associated genes, little is known about the molecular and genetic determinants which are associated with the invasive growth of HNSCC. We hypothesize that the invasive growth of HNSCC may be controlled by a group of unique genes (invasive genes). Since clinical studies have found that the abnormal activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway is associated with the invasion and metastasis of HNSCC and since HGF potently stimulates the invasive growth of HNSCC in several experimental models, in this application, we propose to employ functional genomic approaches to dissect its signaling network and to identify its downstream effectors/molecules. In Aim 1, we propose to identify HGF-induced genes which play an important role in the invasive growth and survival of HNSCC using microan'ay analysis. In Aim 2, we attempt to screen HGF-induced genes which promote invasive growth using a combination of functional assays and cDNA expression library on a genome-wide basis. In Aim 3, we propose to identify novel invasive genes from the invasive/metastatic human tumors. Using tissue microarray, we will confirm whether the expression of newly identified genes is associated with HNSCC invasive growth and metastasis, thereby developing a novel molecular signature of the invasive gene expression for HNSCC. The novel findings from these studies may help us to understand the molecular mechanisms of HNSCC invasive growth and to develop new strategies for the diagnosis, prevention and treatment of HNSCC.